RAS and RAF mutations in banal melanocytic aggregates contiguous with primary cutaneous melanoma: clues to melanomagenesis.
BACKGROUND
Distinguishing banal melanocytic aggregates contiguous with malignant melanoma can be a histological challenge but is essential because of the potential for a spurious Breslow measurement.


OBJECTIVE
Our aim was to ascertain whether the histological distinction between the two relates to differences in the prevalence of mutations in genes significant in melanomagenesis.


METHODS
Mutations in BRAF codon 600, NRAS1 codons 12/13, NRAS2 codons 60/61 and KRAS codons 12/13 were ascertained in 18 cases of primary cutaneous malignant melanoma contiguous with banal melanocytic aggregates using laser capture microdissection.


RESULTS
Overall, 12 of 18 cases (67%) exhibited a mutation in at least one gene. BRAF V600E appeared to be the most commonly mutated gene in both the melanocytic aggregate (seven of 18, 39%) and the melanoma (four of 18, 22%). Both populations demonstrated a similar BRAF genomic profile in 11 of 18 cases (61%) (two BRAF V600E, nine BRAF-WT), a similar KRAS genomic profile in 14 of 18 cases (78%) (one KRAS G12V, 13 KRAS-WT) and a similar NRAS2 genomic profile in 14 of 18 cases (all WT). Of interest, we noted a relatively high prevalence of KRAS mutations (five of 18, 28%). The frequency of KRAS mutations in the melanocytic aggregate (five of 18, 28%) was second to BRAF V600E, while in melanoma, the frequency was also second to BRAF V600E but equalled that of NRAS2 (1 of 18, 6%). No NRAS1 mutations were observed. BRAF and RAS mutations appeared to be mutually exclusive with only three of 18 cases (17%) demonstrating a mutation in both genes (melanocytic aggregate only).


CONCLUSIONS
Our findings hint towards the interpretation of banal melanocytic aggregates serving as precursor lesions.
Dadzie
O E
OE
Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, 609 Albany Street, J-301, Boston, MA 02118, USA.
Yang
S
S
Emley
A
A
Keady
M
M
Bhawan
J
J
Mahalingam
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis; D055088:Early Detection of Cancer; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009508:Nevus, Pigmented / Q000235:genetics / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
D003062:Codon; D018969:Insulin-Like Growth Factor Binding Proteins; C102529:insulin-like growth factor binding protein-related protein 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf